The parent RO1 Does Kidney Function Determine Aging Success made significant advances regarding the clinical importance of mild, age-related decreases in the kidney's filtration function. Despite these advances, however, little is known about how the aging process causes glomerular filtration rate (GFR) decline and the relationships of GFR loss to impairments of other critical functions of the kidney. The conceptual model underlying this proposal is that several types of chronic kidney injury - tubular damage, glomerular leak, interstitial fibrosis, and vascular injury - promote decline in GFR and abnormalities in kidney endocrine function, including 25 vitamin D hydroxylation and erythropoietin production. The resulting abnormalities in mineral metabolism and hemoglobin production, respectively, partially explain the relationships of both GFR and the markers of kidney injury with adverse clinical outcomes. In this revised competitive renewal, we expand from our earlier studies of cystatin C as a novel marker of kidney filtration in a new direction to an evaluation of a comprehensive set of novel kidney injury markers in 1500 participants from the Multiethnic Study of Atherosclerosis (MESA) with a balanced age and race distribution, and 3044 participants from the Health Aging and Body Composition (Health ABC) Study, a cohort of older adults. We also calibrate this set of kidney injury markers with kidney histopathology among 250 kidney donors. Our specific aims are: 1) to evaluate the cross-sectional associations of age with markers of kidney injury in MESA, and the association of markers of kidney injury with histopathology in Cleveland Clinic kidney donors; 2) to evaluate the cross-sectional association of markers of kidney injury with abnormalities in mineral metabolism and hemoglobin production in Health ABC; 3) to determine the association of kidney injury markers with decline in GFR in longitudinal analyses in Health ABC; and, 4) to determine the associations of markers of kidney injury with clinical outcomes of aging in longitudinal analyses in Health ABC. This proposal is directly responsive to the Program Announcement (PA 09-165) Renal Function and CKD in Aging as it evaluates the etiology and pathophysiology of CKD in the elderly, and the epidemiology and risk factors for the development of CKD with advancing age. The investigators have worked together for more than 5 years on the parent R01 and other collaborative projects, have been extremely productive with more than 30 manuscripts published or in press during the period of the parent R01, and include a multidisciplinary team of geriatricians, nephrologists, statisticians, epidemiologists and biomarker experts. PUBLIC HEALTH RELEVANCE: Chronic kidney disease, particularly prevalent in the elderly, is a growing public health problem with enormous impact on morbidity, mortality and resource utilization. In this proposal, we evaluate novel urinary biomarkers and their relationship to aging, decline in kidney function and clinical outcomes. We plan to develop a novel paradigm to define the kidney's aging process; a potential method for the early detection of chronic injury to the kidney; and ultimately novel targets for therapies to reduce the burden of chronic kidney disease in the elderly.